Technetium-99m Sestamibi Tumor Imaging:
Technetium 99m Sestamibi Tumor Imaging General Considerations:
The accumulation of Tc-Sestamibi (Tc-MIBI) in tumors is likely related to a number of variables. Tc-MIBI is a lipophilic monovalent cation (an isonitrile compound). It enters the cell via passive diffusion across plasma and mitochondrial membranes. It is postulated that Tc-MIBI accumulates within the mitochondria and cytoplasm of cells on the basis of electrical potentials generated across the membrane bilayers. At equilibrium it is sequestered largely within mitochondria by a large negative transmembrane potential. The agent is fixed intracellularly as long as cell membrane integrity is intact and nutrient blood flow persists.
Washout of Tc-MIBI from tumor cells is related to the energy (ATP) dependent transmembrane transporter proteins which include the P-glycoprotein pump system (Pgp) and the multidrug resistance protein (MRP) [7,8,38]. Tumor cells with a higher concentration of these transmembrane proteins demonstrate a faster rate of Tc-MIBI clearance (and hence, less tracer uptake) [7,8,22]. MIBI tumor washout can aid in identification of multi-drug resistant tumors and may provide prognostic information [38].
There are many advantages to using Technetium rather than Thallium for scintigraphic imaging. Technetium's shorter physical half-life permits the use of a higher dose of the radiopharmaceutical [37]. This translates to a higher count rate which will shorten imaging times and provide sharper pictures [37]. The gamma energy of Technetium (140 keV) is optimal for use with the detector crystal used in the gamma camera and will undergo less attenuation and scatter. Technetium is also readily available and produced daily from a Molybdenum generator in most Nuclear Medicine departments. Since its introduction, Tc-99m-Sestamibi has been shown to be of value in the evaluation of many tumors.
Bone and Soft Tissue Tumors:
Tc-MIBI has been evaluated for distinguishing benign from malignant bone lesions [22]. Sensitivity has been reported to be 81%, and specificity 87%. Tc-MIBI may be particularly useful in evaluating sites of fracture- pathologic fractures demonstrate increased Tc-MIBI accumulation, while non-pathologic fractures do not [22]. False positive findings can be seen in myositis ossificans, osteoid osteomas, non-ossifying fibromas, and giant cell tumors [22].
Tc-MIBI has also been used in assessing malignant bone and soft tissue tumor response to therapy [28]. Like thallium, uptake is non-specific and can be seen in both benign and malignant lesions. Tc-MIBI permits the acquisition of flow images which are not possible with Thallium. [16]
Despite improved clinical outcome in osteosarcomas patients through the use of multiagent chemotherapy regimens, systemic relapses occur in about 50% of cases [38]. Conventional cytotoxic agents such as doxorubicin used in the treatment of osteosarcoma are substrates of multidrug resistance proteins which can limit the agents effectiveness [38]. Following Tc-MIBI injection, measurement of tumor to background activity at 10 and 60 minutes post injection can be used to determine the percent washout of the agent [38]. A higher washout indicates multidrug resistance protein expression by the tumor and a higher likelihood that the tumor will not have a complete response to therapy [38].
CNS Neoplasms:
Tc-Sestamibi has also been used to evaluate CNS neoplasms. Tc-MIBI uptake is a marker of mitochondrial oxidative capacity. Tc-MIBI uptake correlates with the mitochondrial marker malate dehydrogenase. The addition of the mitochondrial uncoupler CCCP (which contains cyanide) can release 85% of the Tc-MIBI. In patients responding to chemotherapy, Tc-MIBI uptake within the lesion frequently decreases and this is felt to be reflective of damage to the mitochondrial oxidative capacity of the tumor. Unfortunately, choroid plexus activity seen with Tc-sestamibi limits its usefulness for CNS neoplasm imaging [15]. Choroid plexus uptake is not blocked by the use of perchlorate. In a comparison of Tc-MIBI with FDG PET for the detection of recurrent CNS neoplasm, Tc-MIBI was found to be of limited value [40].
Breast Cancer:
For the evaluation of focal breast lesions:
Mammography is the method of choice for the early detection of clinically occult breast cancer [25]. A 30% reduction in mortality has been reported among women enrolled in mammographic screening programs [25]. Screening mammography has a relatively high sensitivity of nearly 90%, but is limited by its lack of specificity which is only about 35-54%, even in specialized centers [23,25]. The utility of mammography is especially limited in patients with large amounts of glandular tissue and dense breasts [25]. Tc-Sestamibi (Tc-MIBI) has been used to evaluate breast lesions, and may be more sensitive than thallium in the evaluation of breast lesions greater than 1.5 cm in size. The Tc-sestamibi examination is not affected by breast density [32]. The typical dose is approximately 20-30 mCi of Tc-Sestamibi. Specially designed imaging systems have been developed to permit prone lateral imaging of the breasts. High resolution planar images are acquired for 10 minutes per view. Early imaging is more sensitive than delayed studies as sestamibi accumulation within breast lesions decreases significantly by one hour after tracer administration [34,36]. Optimum imaging should begin 10 minutes after tracer injection [36]. There may be adherence of tracer in the regional veins after injection making evaluation of the axilla and upper breast suboptimal- the arm opposite the side of the lesion or the foot should therefore be injected. The Tc-MIBI exam is not affected by the density of the breast [6]. Lesions as small as 4 mm can be detected [23]. When combined with conventional mammography the two exams have an overall improved sensitivity for malignancy [21].
Overall, Tc-Sestamibi has a sensitivity of 70-96% and a specificity of 71-100% for determination of breast malignancy [6,19,21,23,25,31,32,34] which is similar to that reported for FDG PET imaging (although FDG images usually demonstrate a greater tumor to normal tissue activity ratio) [19]. The negative predictive value has been reported to be between 81-97%. A comprehensive review of the literature found a total average sensitivity of 84.5%, average specificity of 89%, average positive predictive value of 89%, average negative predictive value of 84%, and an average accuracy of 86% [24]. Most false negative exams occur with lesions smaller than 1 to 1.5 cm in size or non-palpable lesions [21,32,35]. Studies indicate that the exams sensitivity drops to 51% to 72% for non-palpable lesions [2,3,6,20] (and the lower sensitivity is probably more accurate [6]). A recent multicenter prospective trial [20] found an overall institutional sensitivity of 75.4%, a specificity of 82%, a positive predictive value of 74.5%, and a negative predictive value of 83.4% (with a disease prevalence of 40%). In this same study, the sensitivity for tumors under 1 cm in size was only 48.2% [20]. In the European multicenter study, the sensitivity was 71% and the specificity was 69% [41]. Large lesions may also go undetected [21]. In one study, 19% of false-negative exams occurred in lesions over 3 cm in size [31]. Negative exams in large lesions may be related to: 1- overexpression of the multidrug resistance gene; 2- lesions with low desmoplastic activity or low cellular proliferation; and 3- lesions with low cell counts, low vascularity, and absence of inflammation [31,41]. Detection of smaller lesions is improved with the use of a high-resolution breast specific gamma camera, but the equipment costs make such a unit impractical for routine clinical use [35].
False positive exams have been described with fibroadenomas, papillomas, epithelial hyperplasia, mastitis, scleradenosis, and fibrocystic breast disease [1,11,31]. Patients with fibrocystic disease are more likely to have false-positive examinations [6]. It has been noted that high resolution images of the breasts with either thallium or Tc-MIBI may demonstrate some normal glandular activity, but this is usually bilateral and non-localizing in character [1,2]. Washout of tracer from both benign and malignant lesions is variable and does not aid in lesion differentiation [6]. Quantification of uptake has also not been of value in differentiating benign from malignant lesions [6]. Tc-MIBI may be superior to Tc-tetrofosmin for the evaluation of breast malignancies based upon in vitro studies [17]. SPECT images provided better lesion contrast, but were more difficult in determining lesion localization [4]. Also, SPECT images often bring out the non-homogeneous characteristics of patients with fibroglandular breasts resulting in an increased risk for a false-positive interpretation [6].
It is generally accepted that Tc-MIBI is not accurate in the detection of malignant axillary adenopathy (sensitivity 38-60%) [1,2,19], although sensitivities as high as 79% to 84% have been reported [5,10].
Words of caution: Tc-MIBI is not competitive with mammography on either a cost effective or sensitivity basis for screening patients [6]. All articles regarding Tc-MIBI in the evaluation of breast masses suffer from 2 major drawbacks- 1- The reported results for these studies focuses on a preselected patient population- as a result the incidence of cancer in the patients sent for the exam is usually very high 32-84%. This suggests a selection bias and sensitivity of the exam is likely overestimated [9]. 2- The mean lesion size is generally over 1.0 to 1.5 cm- by this size, a lesion will usually have fairly characteristic mammographic or sonographic findings which can aid in differentiating a benign from a malignant lesion [11]. Other drawbacks include the lack of an adequately high negative predictive value which means malignant lesions may be missed [6,11] and false positive exams occur in benign lesions such as fibroadenomas and inflammatory conditions. Biopsy remains the most accurate way to determine whether a lesions is benign or malignant. Stereotactic and ultrasound guided biopsies of breast lesions are minimally invasive and have a high yield to provide a definite diagnosis. Despite optimism in the nuclear medicine literature, this exam probably has only a minor role in selected cases for the evaluation of patients with suspected breast malignancy [18]- such as in patients with palpable masses, but no mammographically detectable abnormality due to dense breasts [31]. However, ultrasound would probably be a better exam to initially evaluate these patients. Unfortunately, none of the Tc-MIBI studies have incorporated breast ultrasound into the patient management scheme. Contrast enhanced dynamic MR imaging can also be used to evaluate lesions under similar circumstances and has been shown to have a higher sensitivity than Tc-MIBI - 96% vs 80% [25].
For the evaluation of multidrug resistance:
Tumor resistance to chemotherapy is in part mediated through an over-expression of the P-glycoprotein pump and other associated multidrug resistant glycoproteins which are the product of the multidrug resistance gene MDR1 [39]. These glycoproteins are responsible for the outward cellular transport of a variety of chemotherapeutic agents (such an daunorubicin, vincristine, and adriamycin) [33,39]. 99mTc-sestamibi is a substrate for the P-glycoprotein pump and a correlation exists between the efflux rate of 99mTc-sestamibi and the expression of P-glycoprotein in breast cancer [33,39]. By performing early and delayed 99mTc-sestamibi imaging of patients with breast cancer the washout rate of sestamibi can be determined. Lack of significant tracer washout indicates a low risk for chemoresistance [33]. On the other hand, a high washout rate was associated with a high probability for chemoresistance (sensitivity 100%, specificity 80%, and positive predictive value 83%) [33]. In these patients, the use of chemorevertant or chemomodulator agents could be justified [33].
Thyroid Cancer:
Tc-MIBI has also been used in the evaluation of metastatic thyroid cancer. The overall sensitivity of Tc-sestamibi for the detection of thyroid cancer ranges from 36% to 89%, and the specificity is 89-100% [37]. Early imaging (10-30 minutes after tracer administration) will detect more lesions [37]. Sestamibi is particularly sensitive for the detection of nodal metastases [37]. The agent has poor sensitivty for the detection of lung metastases and residual neck bed thyroid tissue [37]. The agent is particularly useful for follow-up of high risk patients with elevated thyroglobulin and negative radioiodine scans, and in patients with hurthle cell or medullary carcinoma. [13,14,27,30]
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